SHANK3

SH3 and multiple ankyrin repeat domains 3, the group of Sterile alpha motif domain containing|Ankyrin repeat domain containing|PDZ domain containing

Basic information

Region (hg38): 22:50674408-50733212

Links

ENSG00000251322 ∙ NCBI:85358 ∙ OMIM:606230 ∙ HGNC:14294 ∙ Uniprot:Q9BYB0 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Phelan-McDermid syndrome (Strong), mode of inheritance: AD
• Phelan-McDermid syndrome (Strong), mode of inheritance: AD
• Phelan-McDermid syndrome (Strong), mode of inheritance: AD
• Phelan-McDermid syndrome (Strong), mode of inheritance: AD
• schizophrenia 15 (Limited), mode of inheritance: AD
• Phelan-McDermid syndrome (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Phelan-McDermid syndrome; Schizophrenia 15	AD	General	There is evidence that variants in this gene are also involved in autism-related disorders; Deletions have been described as responsible for feaures of Chromosome 22q13.3 deletion syndrome; Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Craniofacial; Neurologic	12920066; 17173049; 17999366; 12920066; 20301377; 20385823; 21150887; 21376300; 21606927; 22892527; 22922660
There is evidence that variants in this gene are also involved in autism-related disorders; Deletions have been described as responsible for features of Chromosome 22q13.3 deletion syndrome

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SHANK3 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SHANK3 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				1		1
missense			1	1		2
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region			1			1
non coding			3	2	3	8
Total	0	0	4	4	3

Variants in SHANK3

This is a list of pathogenic ClinVar variants found in the SHANK3 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
22-50674422-T-C			Uncertain significance (Nov 01, 2022)
22-50674428-GCGC-G			Likely benign (Feb 01, 2023)
22-50674428-G-GCGC			Benign (Jun 01, 2024)
22-50674428-G-GCGCCGC			Likely benign (Nov 01, 2023)
22-50674455-C-T			Uncertain significance (Aug 01, 2024)
22-50674484-G-T			Likely benign (Jun 01, 2024)
22-50674539-G-C			Uncertain significance (Aug 01, 2022)
22-50674569-G-A		Phelan-McDermid syndrome	Uncertain significance (Dec 14, 2022)
22-50674573-CCG-C			Benign (Jul 27, 2018)
22-50674638-G-T		Inborn genetic diseases	Conflicting classifications of pathogenicity (Mar 18, 2021)
22-50674678-G-C			Likely benign (Jun 11, 2021)
22-50674689-G-A			Likely benign (Aug 01, 2023)
22-50674700-A-G		Inborn genetic diseases	Uncertain significance (Aug 19, 2020)
22-50674710-C-T		Inborn genetic diseases	Uncertain significance (Jul 05, 2022)
22-50674726-C-T			Benign (May 08, 2021)
22-50675029-C-G			Likely benign (Jan 27, 2021)
22-50675030-G-A			Benign/Likely benign (Apr 09, 2020)
22-50675071-C-A			Likely benign (Mar 01, 2024)
22-50675074-G-A		SHANK3-related disorder	Likely benign (May 19, 2021)
22-50675077-C-G		Inborn genetic diseases	Likely benign (Sep 17, 2020)
22-50675078-G-T		Phelan-McDermid syndrome	Uncertain significance (Mar 08, 2020)
22-50675089-C-T		Inborn genetic diseases	Likely benign (Oct 23, 2019)
22-50675093-C-T			Uncertain significance (Jan 27, 2023)
22-50675094-A-C		Phelan-McDermid syndrome	Likely benign (Dec 21, 2022)
22-50675109-C-T			Uncertain significance (Apr 01, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SHANK3	protein_coding	protein_coding	ENST00000262795	23	58884

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	2.53e-7	124105	0	2	124107	0.00000806

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.74	571	884	0.646	0.0000599	10881
Missense in Polyphen		197	427.26	0.46108		4590
Synonymous	-3.40	492	405	1.21	0.0000297	3824
Loss of Function	6.36	2	51.0	0.0392	0.00000262	666

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00000895	0.00000891
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.000167	0.000166

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Major scaffold postsynaptic density protein which interacts with multiple proteins and complexes to orchestrate the dendritic spine and synapse formation, maturation and maintenance. Interconnects receptors of the postsynaptic membrane including NMDA-type and metabotropic glutamate receptors via complexes with GKAP/PSD-95 and HOMER, respectively, and the actin-based cytoskeleton. Plays a role in the structural and functional organization of the dendritic spine and synaptic junction through the interaction with Arp2/3 and WAVE1 complex as well as the promotion of the F-actin clusters. By way of this control of actin dynamics, participates in the regulation of developing neurons growth cone motility and the NMDA receptor-signaling. Also modulates GRIA1 exocytosis and GRM5/MGLUR5 expression and signaling to control the AMPA and metabotropic glutamate receptor- mediated synaptic transmission and plasticity. May be required at an early stage of synapse formation and be inhibited by IGF1 to promote synapse maturation. {ECO:0000269|PubMed:24132240}.
• Disease: DISEASE: Note=A chromosomal aberration involving SHANK3 is found in patients with chromosome 22q13.3 deletion syndrome. Translocation t(12;22)(q24.1;q13.3) with APPL2/DIP13B. {ECO:0000269|PubMed:11431708}.; DISEASE: Note=Defects in SHANK3 are associated with neuropsychiatric disorders such as autism spectrum disorders (ASD), bipolar affective disorders and early dementia onset. ASD are characterized by impairments in reciprocal social interaction and communication as well as restricted and stereotyped patterns of interest and activities. ASD include forms with moderate to severe cognitive impairment and milder forms with higher cognitive ability (Asperger syndrome). Gene duplication is associated with hyperkinetic neuropsychiatric disorders (PubMed:24153177) such as hyperactivity, auditory overstimulation, epilepsy and bipolar affective disorders, among others. {ECO:0000269|PubMed:24153177}.; DISEASE: Phelan-McDermid syndrome (PHMDS) [MIM:606232]: A developmental disorder with variable features. Common features include neonatal hypotonia, global developmental delay, normal to accelerated growth, absent to severely delayed speech, autistic behavior, and minor dysmorphic features. {ECO:0000269|PubMed:22892527, ECO:0000269|PubMed:23758760, ECO:0000269|PubMed:24132240}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Schizophrenia 15 (SCZD15) [MIM:613950]: A complex, multifactorial psychotic disorder or group of disorders characterized by disturbances in the form and content of thought (e.g. delusions, hallucinations), in mood (e.g. inappropriate affect), in sense of self and relationship to the external world (e.g. loss of ego boundaries, withdrawal), and in behavior (e.g bizarre or apparently purposeless behavior). Although it affects emotions, it is distinguished from mood disorders in which such disturbances are primary. Similarly, there may be mild impairment of cognitive function, and it is distinguished from the dementias in which disturbed cognitive function is considered primary. Some patients manifest schizophrenic as well as bipolar disorder symptoms and are often given the diagnosis of schizoaffective disorder. {ECO:0000269|PubMed:20385823}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Glutamatergic synapse - Homo sapiens (human);Developmental Biology;Neuronal System;Signaling events regulated by Ret tyrosine kinase;Neurexins and neuroligins;RET signaling;Axon guidance;Protein-protein interactions at synapses (Consensus)

Recessive Scores

• pRec: 0.111

Haploinsufficiency Scores

• pHI: 0.198
• hipred: Y
• hipred_score: 0.718
• ghis: 0.555

Essentials

• essential_gene_CRISPR2: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.794

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	High
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Shank3
• Phenotype: homeostasis/metabolism phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; taste/olfaction phenotype; hearing/vestibular/ear phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); limbs/digits/tail phenotype; vision/eye phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span)

Zebrafish Information Network

• Gene name: shank3a
• Affected structure: Rohon-Beard neuron
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: MAPK cascade;axon guidance;synapse assembly;learning;memory;striatal medium spiny neuron differentiation;adult behavior;negative regulation of actin filament bundle assembly;social behavior;vocal learning;negative regulation of cell volume;positive regulation of long-term neuronal synaptic plasticity;brain morphogenesis;synaptic growth at neuromuscular junction;positive regulation of synapse structural plasticity;positive regulation of synaptic transmission, glutamatergic;long-term synaptic potentiation;dendritic spine morphogenesis;positive regulation of dendritic spine development;regulation of dendritic spine morphogenesis;vocalization behavior;postsynaptic density assembly;AMPA glutamate receptor clustering;NMDA glutamate receptor clustering;guanylate kinase-associated protein clustering;regulation of long-term synaptic potentiation;positive regulation of long-term synaptic potentiation;positive regulation of glutamate receptor signaling pathway;regulation of long-term synaptic depression;regulation of AMPA receptor activity;positive regulation of excitatory postsynaptic potential;positive regulation of AMPA receptor activity
• Cellular component: cytosol;ionotropic glutamate receptor complex;postsynaptic density;cell junction;dendrite;extrinsic component of cytoplasmic side of plasma membrane;neuron projection;dendritic spine;neuron spine;postsynaptic membrane;ciliary membrane
• Molecular function: actin binding;protein binding;protein C-terminus binding;zinc ion binding;SH3 domain binding;receptor signaling complex scaffold activity;GKAP/Homer scaffold activity;ionotropic glutamate receptor binding;protein self-association;scaffold protein binding